regulation of blood sugar level at the whole animal owen m c guinness january 11, 2010 course: mpb...
TRANSCRIPT
Regulation of Blood Sugar Level Regulation of Blood Sugar Level at the Whole Animalat the Whole Animal
Owen MOwen MccGuinnessGuinness
January 11, 2010January 11, 2010
Course: MPB 333
Contact info:Phone: 343-4473Office: 831C Light Halle-mail:[email protected]
Regulation of Glucose Regulation of Glucose Homeostasis: the Metabolic Homeostasis: the Metabolic
Challenge of Insulin ResistanceChallenge of Insulin Resistance
What is a normal fasting What is a normal fasting Glucose concentration?Glucose concentration?
Normal fasting Normal fasting level=<110 mg/dllevel=<110 mg/dl
Impaired glucose Impaired glucose intolerance=110-intolerance=110-125 mg/dl125 mg/dl
Diabetes Diabetes mellitus>125mg/dlmellitus>125mg/dl
Where is glucose?Where is glucose?
ISF CellCapillary
DiffusionGlucose
=100 mg/dl
Glucose=? mg/dl
Glucose diffuses down a Glucose diffuses down a concentration gradientconcentration gradient
If the arterial glucose=100 mg/dl and insulin is If the arterial glucose=100 mg/dl and insulin is at a basal concentration, what is the glucose at a basal concentration, what is the glucose
concentration in a muscle cell?concentration in a muscle cell?
1.1. 100 mg/dl100 mg/dl
2.2. Slightly less than 100 mg/dl Slightly less than 100 mg/dl (~98 mg/dl)(~98 mg/dl)
3.3. Very low ~2 mg/dlVery low ~2 mg/dl
4.4. Greater than 100 mg/dlGreater than 100 mg/dl
Blood flow
Cell
Glu-6P
Glu
A VGLU= 100 mg/dl GLU= 98 mg/dl
3. Very low ~2 mg/dl
Glucose
Glucose-6 P
Glycogen
Pyruvate
Lactate
CO2 + H2O
GLUT
HK II
Multiple Metabolic Fates of Glucose
GSPFK
PDH
If arterial glucose=100 mg/dl ,what is the If arterial glucose=100 mg/dl ,what is the interstitialinterstitial glucose concentration outside a glucose concentration outside a
muscle cell?muscle cell?
1.1. 100 mg/dl100 mg/dl
2.2. Slightly less than 98 mg/dlSlightly less than 98 mg/dl
3.3. Very low ~2 mg/dlVery low ~2 mg/dl
4.4. Greater than 100 mg/dlGreater than 100 mg/dl
A V
Blood flow
Cell
GLU= 100 mg/dl GLU= 98 mg/dl
Glu-6P
Glu
#2. Slightly less than 98 mg/dl
Steady StateSteady State
In=Out
Out=Clearance x Concentration
Plasma Glucose
Relationship between Mass and Relationship between Mass and ConcentrationConcentration
Volume
Injected MassC ononcentrati
Glucose mass (70 kg individual)Glucose mass (70 kg individual)
Total body water (TBW)=60% Body WeightTotal body water (TBW)=60% Body Weight 42 L TBW (=0.60 *70 kg)42 L TBW (=0.60 *70 kg) Extracellular fluid volume (ECF)=1/3 TBWExtracellular fluid volume (ECF)=1/3 TBW 14 L ECF {~volume of distribution of glucose}14 L ECF {~volume of distribution of glucose} Glucose 100 mg/dl=1 mg/ml=1 g/LGlucose 100 mg/dl=1 mg/ml=1 g/L 14 grams glucose in ECF14 grams glucose in ECF 9 g/hr flux rate= rate of liver glucose production9 g/hr flux rate= rate of liver glucose production
Glucose Ingestion (75 g)Glucose Ingestion (75 g)
In=Out=9 g/h
Out=Clearance x Concentration
Plasma Glucose(14 g)
Ingest 75 grams glucoseIngest 75 grams glucose
75 grams in 300 ml water (~2 cokes)75 grams in 300 ml water (~2 cokes) Assuming it takes about 20 min to Assuming it takes about 20 min to
absorb the glucose (225 g/h)absorb the glucose (225 g/h) By 180 minutes the glucose By 180 minutes the glucose
concentration returns to normalconcentration returns to normal Removed 5.3 times the mass of Removed 5.3 times the mass of
glucose in the body in 180 minglucose in the body in 180 min
Time (min)
0 60 120 180
Glu
co
se (
mg
/dl)
0
100
200
300
400
NormalDiabetic
75 grams
75 g glucose load75 g glucose load
If you did nothingIf you did nothing glucose level exceed 500 mg/dlglucose level exceed 500 mg/dl
Liver9 g/hr
Glucose=90 mg/dl
CNS
Brain6 g/hr
MuscleFat
3 g/hr
Insulin++
GlucagonInsulin
Overnight fasted state
? ?
Liver 12 g/hrGlucose=~130 mg/dl
CNS
Brain6 g/hr
MuscleFat32 g/hr
Insulin
++
or GlucagonInsulin
Fed state
Intestine50 g/hr
Cholinergic
Liver7 g/hr
Glucose=~70 mg/dl
CNS
Brain~5 g/hr
MuscleFat2 g/hr
Insulin
++
GlucagonInsulin
Prolonged fasted state
Ketones
Liver46 g/hr
Glucose=~90 mg/dl
CNS
Brain6 g/hr
MuscleFat
40 g/hr
Insulin
++
GlucagonInsulin
“Fight or Flight” state
Adrenergic
Increased Muscle Energy
Demand
Liver26 g/hr
Glucose>~300 mg/dl
CNS
Brain6 g/hr
MuscleFat<1 g/hr
+
Glucagon
Type I Diabetic state ( loss of insulin secretion)
Kidney~19 g/hrKetones
Net Organ UptakeNet Organ Uptake
(A-V) * flow = uptake
Hepatic vein
Net Splanchnic uptakeNet Splanchnic uptake
(Artery-HepaticVein) * flow = uptake
Splanchnic bed:liverIntestineSpleenpancreas
Splanchnic BedSplanchnic Bed
Producer and/or glucose consumerLiverIntestine
Splanchnic metabolism during hyperglycemiaSplanchnic metabolism during hyperglycemia
Persistent glucose Persistent glucose production in diabetic production in diabetic (i.e. negative balance)(i.e. negative balance)
Failure to take up Failure to take up glucose with glucose with additional insulinadditional insulin
The failure to activate The failure to activate uptake and suppress uptake and suppress production both production both contributecontribute
DiabeticNon-Diabetic
Low insulin High insulin
Individuals with type II diabetes Individuals with type II diabetes The liver produces glucose The liver produces glucose despite high glucose levels despite high glucose levels
Glucose Concentration(mg/dl)
50 100 150 200
Glucose Uptake(mg/kg/min)
2
4
6
8
10
12
50 100 150 2000
2
4
6
8
10
12
Glucose Uptake(mg/kg/min)
Glucose Concentration(mg/dl)
4x insulin
basal insulin
4x insulin
basal insulin
Tissue glucose uptake Tissue glucose uptake increases in proportion increases in proportion to the available glucoseto the available glucose
Insulin facilitates this Insulin facilitates this process in tissues that process in tissues that respond to insulinrespond to insulin transporttransport phosphorylationphosphorylation– ↑↑Glycogen synthesisGlycogen synthesis– ↑↑Glucose oxidationGlucose oxidation
Insulin resistance Insulin resistance impairs this processimpairs this process
Insulin Resistant
Normal
Steady StateSteady State
In=Out
Out=Clearance x Concentration
Plasma Glucose
Source: www.cdc.gov.
Diabetes Trends* Among Adults in the Diabetes Trends* Among Adults in the U.S.,U.S.,
(Includes Gestational Diabetes)BRFSS,(Includes Gestational Diabetes)BRFSS, 1990,1995 and 20011990,1995 and 20011990 1995
2001
No Data <4% 4%-6% 6%-8% 8%-10% >10%
Liver9 g/hr
Glucose=120 mg/dl
CNS
Brain6 g/hr
MuscleFat
3 g/hr
Insulin
++
GlucagonInsulin
Overnight Fasted Insulin Resistant state
Compensation for insulin Compensation for insulin resistanceresistance
Increase insulin secretionIncrease insulin secretion Mild to severe hyperglycemia Mild to severe hyperglycemia
(Diabetes Type II; NIDDM) because (Diabetes Type II; NIDDM) because of inadequate pancreas compensationof inadequate pancreas compensation
Glucose production by liver and Glucose production by liver and uptake by peripheral tissues can be uptake by peripheral tissues can be normal or increasednormal or increased
Tools used in vivo to assess Tools used in vivo to assess glucose homeostasis and insulin glucose homeostasis and insulin
actionaction
MEASUREMENT OF GLUCOSE PRODUCTION IN VIVO
Tracer Method ( dilution principle)
3-3H Glucose infusion
Data analysis with two compartment model
A-V Difference Method
Blood glucose difference across organ
Blood flow across organ
x
-40
-20
0
20
40
0
100
200
300
-40 0 60 120 180
0
50
100
150
200
TIME ( MIN )
SENSITIVITY OF & CELLS TO GLUCOSE IN VIVO
ARTERIALPLASMAINSULIN
% BASAL
ARTERIALPLASMA
GLUCAGON
% BASAL
ARTERIALPLASMA
( mg/dl )
GLUCOSE
Gly Inhibitor + Glucose
0
2
4
ARTERIAL PLASMA GLUCOSE
( mg/dl )
EFFECT OF GLUCOSE ON INSULIN AND GLUCAGON
INSULIN
SECRETION
( pmol/kg/min )
50 75 100 125 150
0.0
0.4
0.8
GLUCAGON
SECRETION
( ng/kg/min )
SECRETION IN THE CONSCIOUS DOG
Flattem et al.: Diabetes 50, February 2001: 367-375
FastingGlucose
FastingGlucose
Sampling site: Portal Vein and Sampling site: Portal Vein and ArteryArtery
If you infuse a substance into the If you infuse a substance into the portal vein, the concentration of the portal vein, the concentration of the substance in the portal vein will be substance in the portal vein will be greater than in any other vesselgreater than in any other vessel
0
50
100
0
50
100
-40 0 60 120 180
0
50
100
TIME ( Min )
EFFECT OF A SELECTIVE INCREASE IN INSULIN
-40 0 60 120 180
0
50
100
TIME ( Min )
Pancreatic ClampInsulin
Pancreatic ClampSaline
Portal
Arterial
Portal
Arterial
PLASMA
INSULIN
( U/ml )
PLASMA
GLUCAGON
( pg/ml )
Impact of insulin on tissuesImpact of insulin on tissues
Enhance muscle glucose uptakeEnhance muscle glucose uptake Decrease liver glucose productionDecrease liver glucose production Decrease arterial glucose levelDecrease arterial glucose level Inhibit lipolysisInhibit lipolysis To prevent hypoglycemia exogenous To prevent hypoglycemia exogenous
glucose is givenglucose is given
The “gold standard” for The “gold standard” for quantifying insulin sensitivity quantifying insulin sensitivity in in
vivovivo
Primed-constantInsulin Infusion
VariableGlucose Infusion
Insulin
Glucose
RadioactiveGlucose Tracers
EndogenousGlucose Production (basal and clamp)
GlucoseDisappearance (Rd)
ExogenousGlucose Infusion rate (GIR)
Defronzo RA et al AJP E214,1979
Peripheral insulin sensitivityPeripheral insulin sensitivity
Insulin (U/ml)
0 100 200 300 700
Glu
cose
uti
liza
tio
n(m
g/k
g/m
in)
0
2
4
6
8
10
12
14
0
1
2
3
0
100
200
-40 0 60 120 180
0
1
2
3
TIME ( Min )
EFFECT OF A SELECTIVE INCREASE IN INSULIN
-40 0 60 120 180
0
1
2
3
Control
GLY
( mg/kg/min )
NET
GNG
( mg/kg/min )
FLUX
GLUCOSEPLASMA
( mg/dl )
ARTERIAL
OUTPUTGLUCOSE
( mg/kg/min )
HEPATICNET
TIME ( Min )
Pancreatic Clamp Pancreatic Clamp
+/- Insulin +/- Insulin
Insulin
Hepatic Insulin SensitivityHepatic Insulin Sensitivity
Insulin (U/ml)
0 25 50 75
Glu
cose
Pro
duct
ion
(mg/
kg/m
in)
0
1
2
3
4
5
Human
Basal Insulin
Peripheral vein
Diabetes and insulin resistanceDiabetes and insulin resistance
Insulin resistanceInsulin resistance– Normal or elevated insulin levelsNormal or elevated insulin levels– Inappropriately increased lipolysisInappropriately increased lipolysis– Insulin ineffective and in many cases Insulin ineffective and in many cases
pancreatic defects limit adaptationpancreatic defects limit adaptation– Underlying inflammation can aggravate Underlying inflammation can aggravate
defectsdefects
The EndThe End